Benign prostatic hyperplasia (BPH) is a benign adenoma derived from a transitional region of the prostate which is present surrounding the urethra. Patients with BPH complain of bladder outlet obstructive symptoms or bladder irritative symptoms. Examples of the bladder outlet obstructive symptoms include the delayed initiation of micturition, abdominal muscle straining to void, reduced urinary flow rate, intermittency of urinary stream, post micturition dribble, prolonged voiding time, overflow incontinence, and the like. Examples of the bladder irritative symptoms include increased urinary frequency in the daytime or nighttime, urinary urgency, feeling of incomplete emptying, reduced voided volume during a single micturition, and the like. Functional obstruction and mechanical obstruction are involved in the development of these urinary disturbances due to BPH. These functional obstruction and mechanical obstruction further cause secondary changes in detrusor or nerves, and induce complex morbid states involving bladder irritative symptoms and bladder outlet obstructive symptoms.
As the therapeutic drug for BPH, for example, α1-adrenoceptor blockers, anti-androgen drugs, plant preparations, amino acid preparations or the like are used. Among these, examples of the α1-adrenoceptor blockers include tamusulosin hydrochloride, prazosin hydrochloride, terazosin hydrochloride, urapidil, and the like. As the anti-androgen drugs, chlormazinone acetate, allylestrenol, gestonorone caproate, oxendolone, finasteride or the like are used. The α1-adrenoceptor blockers inhibit functional obstruction of the urethra, by inhibiting the contraction of prostate smooth muscles induced by activation of α1-adrenoceptors with noradrenaline secreted from the sympathetic nerve. The anti-androgen drugs inhibit mechanical obstruction, by ameliorating the prostatic hyperplasia itself and thus reducing the urethra. However, the α1-adrenoceptor blockers and the anti-androgen drugs are effective only for the bladder outlet obstructive symptoms of BPH, but their effects for improving bladder irritative symptoms are usually insufficient. The plant preparations and amino acid preparations have an anti-inflammatory activity, an anti-edema activity, or the like and can improve the symptoms by alleviating the transitional disorder in the bladder neck; however, their effects are weak and the dose required is large so that they are a burden to the BPH patients that are usually old. Also, since there is a risk of causing increased residual urine and urinary retention for using anti-cholinergic agents, the use of anti-cholinergic agents is prohibited or restricted for the patients with BPH. Currently, there is no drug available that alleviates the bladder irritative symptoms associated with BPH.
Storage and voiding of urine are physiologically controlled by complex reflex pathways including peripheral and central nervous systems (Urology, 50 Suppl. 6A: 36–52 (1997)). Feeling of the filled bladder is transferred to the central nervous system via two bladder afferent neurons, the Aδ-fiber and the C-fiber. Under the normal condition, the C-fiber is not involved in the urine voiding (silent); however, the C-fiber is known to be activated and involved in the irritable bladder (Clinical J. Pain, 16, S86–89 (2000)). Moreover, about 70% of BPH patients show the positive reaction to the ice water test, indicating the activated sensory C-fiber, and the patients frequently show bladder irritative symptoms accompanied by the activation of C-fiber (J. Urol., 160: 34–38 (1998)). Also, it has been shown that sprouting of sensory nerves occurs in the spinal cord of a rat in which urethra is partially obstructed, as is the case with BPH (J. Comp. Neurol., 310: 401–410 (1991)). Since such sensory nerves showing sprouting exhibit capsaicin sensitivity, the nerves are the C-fiber, and thus activation of the C-fiber has been confirmed in rats with the bladder outlet obstruction. Collectively, there is accumulating evidence that the C-fiber is involved in the development of bladder irritative symptoms associated with BPH.
The potassium (K+) channel is present on cell membranes of various tissues and shows various physiological activities via the control of membrane potential. The K+ channel is classified into various types depending on the voltage-dependency, Ca++-sensitivity, and other properties of the channel. The slowly-inactivating A-type K+ channel is expressed in capsaicin-sensitive dorsal root ganglion (DRG) cells (J. Neurophysiol., 75: 2629–2646 (1996)), and controls excitability of the C-fiber (J. Physiol., 494: 1–16 (1996)).